CN114945568B - Process for preparing pyrrolidinyl urea derivatives - Google Patents

Process for preparing pyrrolidinyl urea derivatives Download PDF

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CN114945568B
CN114945568B CN202180008843.4A CN202180008843A CN114945568B CN 114945568 B CN114945568 B CN 114945568B CN 202180008843 A CN202180008843 A CN 202180008843A CN 114945568 B CN114945568 B CN 114945568B
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reaction system
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CN114945568A (en
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黄进明
于娟
曾金香
杨丽美
殷婷婷
张杨
伍文韬
李志祥
秦健
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Zhangzhou Pientzehuang Pharmaceutical Co Ltd
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The invention discloses a TrkA inhibitorA process for the preparation of pyrrolidinyl urea derivatives, intermediate compounds of the compounds of formula (I) and a process for their preparation are also disclosed.

Description

Process for preparing pyrrolidinyl urea derivatives
The present application claims priority as follows
CN202010027384.1, filing date: 2020-01-10.
Technical Field
The invention relates to a preparation method of pyrrolidinyl urea derivatives serving as TrkA inhibitors, and also relates to an intermediate compound of a compound shown in a formula (I) and a preparation method of the intermediate compound.
Background
Tropomyosin-related kinase (Trk) is a high affinity receptor tyrosine kinase activated by a group of soluble growth factors known as Nerve Growth Factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophic factor (NT), the family of which consists of three members (TrkA, trkB, trkC). NGF, BDNF, NT-4/5 plays an important role in many physiological regulation processes such as signal maintenance of neuronal cells, signal transmission of neuronal cells, cell proliferation, cell differentiation, cell survival, etc. through the receptor Trk. There is much evidence that inhibitors of NGF/Trk signaling pathways are effective in many preclinical models of pain; inhibitors of NGF/Trk signaling pathways have also been shown to be effective in many preclinical models of inflammatory diseases. In addition, overexpression, activation, amplification and/or mutation of Trk kinase is associated with many tumors or cancers. Therefore, trk becomes an important therapeutic target, and attracts extensive research and development interest. The TrkA inhibitors of the present invention address the need for treatment of pain, cancer, inflammation, neurodegenerative diseases, and certain infectious diseases.
Single compounds having inhibitory activity against TrkA and pharmaceutically acceptable salts thereof are reported in WO 2015175788. A series of compounds having an inhibitory activity against TrkA comprising the pyrrolidinyl urea structures used in the present invention are reported in the WO2012158413, WO2016116900, WO2016021629, WO2017006953 patents.
Disclosure of Invention
The invention provides a process for the preparation of a compound of formula (I),
which comprises the following steps:
step 1: reacting a compound of formula SM3-9 with a compound of formula SM3-10 to obtain a compound of formula SM3-11,
step 2: reacting an intermediate compound obtained by reacting a compound of formula SM1 with a compound of formula 1-1 with a compound of formula SM2 to obtain a compound of formula 1-2,
wherein,
reagent P is selected from acetonitrile;
reagent S-1 is selected from potassium acetate;
the reagent S-2 is selected from tricyclohexylphosphine, 2-di-tert-butylphosphino-3, 4,5, 6-tetramethyl-2, 4, 6-triisopropyl-1, 1-biphenyl, 2- (dicyclohexylphosphino) -3, 6-dimethoxy-2-4-6-triisopropyl-1, 1-biphenyl, triphenylphosphine and 2-dicyclohexylphosphorus-2, 4, 6-triisopropylbiphenyl;
the catalyst U is selected from palladium acetate, diphenylphosphine ferrocene palladium dichloride, tetraphenylphosphine palladium, allyl palladium chloride dimer, cinnamyl palladium chloride dimer and palladium trifluoroacetate;
the base T is selected from sodium carbonate, cesium carbonate and potassium carbonate;
solvent V is selected from dioxane, methylcyclopentyl ether, toluene, methyltetrahydrofuran and tetrahydrofuran.
In some embodiments of the present invention, the above-described preparation method comprises the following reaction scheme:
wherein,
reagent A is selected from 2-methoxyethylamine;
solvent B is selected from tetrahydrofuran;
reagent C is selected from acetyl chloride;
reagent D is selected from acetyl chloride;
solvent E is selected from ethanol;
the reducing agent F is selected from lithium aluminum hydride (flake), borane tetrahydrofuran solution and borane dimethyl sulfide complex;
solvent G is selected from tetrahydrofuran;
reagent H is selected from sulfonic acid isocyanate;
reagent I is selected from tertiary butanol;
base J is selected from triethylamine and diisopropylethylamine;
solvent K is selected from dioxane and dichloromethane;
reagent L is selected from the group consisting of potassium phthaloyl, sodium hydrogen, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate and 1, 8-diazabicyclo undec-7-ene/phthalamide;
the solvent M is selected from N, N-dimethylformamide, tetrahydrofuran, methanol, dioxane and dimethyl sulfoxide;
reagent N is selected from hydrazine hydrate;
the solvent O is selected from ethanol;
reagent Q is selected from p-toluenesulfonic acid, hydrochloric acid and trifluoroacetic acid;
the solvent R is selected from tetrahydrofuran, dichloromethane and ethyl acetate;
the base W is selected from pyridine, triethylamine, diisopropylethylamine and sodium bicarbonate;
the solvent X is selected from dichloromethane, N-dimethylformamide, tetrahydrofuran and ethyl acetate;
the base Y is selected from sodium carbonate, diisopropylethylamine, triethylamine, pyridine, sodium bicarbonate, potassium carbonate and sodium hydroxide;
the solvent Z is selected from tetrahydrofuran/water, methyltetrahydrofuran, methylene chloride and methyltetrahydrofuran/water.
In some embodiments of the present invention, the above preparation method, wherein in the step of preparing the compound SM3-11, the temperature range of the reaction system is controlled to 65.+ -. 5 ℃.
In some embodiments of the present invention, the above-described preparation method, wherein the molar ratio of compound SM3-9 to compound SM3-10 is 1:1.2-2.
In some embodiments of the present invention, the above-mentioned preparation method, wherein the molar ratio of the compound SM1 to the catalyst U is 1:0.05-0.1.
In some embodiments of the present invention, the above preparation method, wherein, in the step of preparing the compound SM3-3, the temperature range of the reaction system is controlled to be 0±5 ℃ when the material is fed into the reaction system.
In some embodiments of the invention, the above-described preparation method, wherein the molar ratio of compound SM3-3 to reagent C is 1:12-17.
In some embodiments of the present invention, the above preparation method, wherein, in the step of preparing the compound SM3-5, the temperature range of the reaction system is controlled to be 0±5 ℃ when the compound SM3-5 is fed into the reaction system.
In some embodiments of the present invention, the above-mentioned preparation method, wherein in the step of preparing the compound SM3-6, the molar ratio of the compound SM3-5 to the reducing agent F is 1:2-4.
In some embodiments of the present invention, the above preparation method, wherein, in the step of preparing the compound SM3-7, the temperature range of the reaction system is controlled to be 15±5 ℃ when the compound SM3-7 is fed into the reaction system.
In some embodiments of the present invention, in the preparation method, in the step of preparing the compound SM3-7, the temperature range of the reaction system is controlled to be 20±5 ℃ after the reagent is dosed.
In some embodiments of the present invention, the above preparation method, wherein, in the step of preparing the compound SM3-7, filtration is maintained under nitrogen atmosphere after completion of the reaction.
In some embodiments of the present invention, in the preparation method, in the step of preparing the compound SM3-7, the temperature range of the reaction system is controlled to be 80±5 ℃ after the reagent is dosed.
In some embodiments of the present invention, the above-mentioned preparation method, wherein in the step of preparing the compound SM3-8, the post-treatment is controlled to be 2.7 to 3.5 when the pH is adjusted with an acid.
In some embodiments of the present invention, the above-mentioned preparation method, wherein in the step of preparing the compound SM3-8, the post-treatment adjusts the pH to control the temperature range of the reaction system to 35±5 ℃.
In some embodiments of the present invention, the above-described preparation method, wherein the molar ratio of the compound SM3-8 to the reagent N is 1:1.5-2.
In some embodiments of the invention, the above-described preparation method, wherein the molar ratio of the compound SM3-11 to the reagent Q is 1:2.5-4.
In some embodiments of the present invention, the above-mentioned preparation method, wherein, in the step of preparing the compounds 1 to 4, the temperature of the reaction system is controlled to be 5.+ -. 5 ℃ when the materials are fed into the reaction system.
In some embodiments of the present invention, the above-mentioned preparation method, wherein in the step of preparing the compounds 1 to 4, the reaction time is 1.5.+ -. 0.5 hours after the completion of the reagent feeding.
In some embodiments of the invention, the above-described methods of preparation, wherein the molar ratio of compounds 1-4 to base Y is 1:5.
Definition and description
The following terms and phrases used herein are intended to have the following meanings unless otherwise indicated. A particular phrase or terminology, unless otherwise specifically defined, should not be construed as being ambiguous or otherwise clear, but rather should be construed in a generic sense. When trade names are presented herein, it is intended to refer to their corresponding commercial products or active ingredients thereof.
Intermediate compounds of the present invention may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent alternatives well known to those skilled in the art, preferred embodiments including but not limited to the examples of the present invention.
The chemical reactions of the embodiments of the present invention are accomplished in a suitable solvent that is compatible with the chemical changes of the present invention and the reagents and materials required therefor. In order to obtain the compounds of the present invention, it is sometimes necessary for a person skilled in the art to modify or select the synthesis steps or reaction schemes on the basis of the embodiments already present.
An important consideration in any synthetic route planning in the art is the selection of the appropriate protecting group for the reactive functional group (e.g., amino group in the present invention).
The compounds of the present invention may be structured by conventional methods well known to those skilled in the art, and if the present invention relates to the absolute configuration of a compound, the absolute configuration may be confirmed by conventional means in the art. For example, single crystal X-ray diffraction (SXRD), the grown single crystal is collected from diffraction intensity data using a Bruker D8 vent diffractometer, and the light source is cukα radiation, scanning:after scanning and collecting the relevant data, the absolute configuration can be confirmed by further analyzing the crystal structure by a direct method (Shellxs 97).
The present invention will be specifically described by the following examples, which are not meant to limit the present invention in any way.
All solvents used in the present invention are commercially available and can be used without further purification.
The invention adopts the following abbreviations: aq represents water; eq represents equivalent, equivalent; DCM represents dichloromethane; PE represents petroleum ether; DMF represents N, N-dimethylformamide; DMSO represents dimethylsulfoxide; etOAc represents ethyl acetate; etOH stands for ethanol; meOH represents methanol; CBz represents benzyloxycarbonyl, an amine protecting group; BOC represents that tert-butoxycarbonyl is an amine protecting group; HOAc stands for acetic acid; r.t. stands for room temperature; rt represents a retention time; O/N stands for overnight; THF represents tetrahydrofuran; boc2O represents di-tert-butyl dicarbonate; TFA stands for trifluoroacetic acid.
Compounds are either prepared according to the general nomenclature of the art or are usedSoftware naming, commercial compounds are referred to by vendor catalog names.
Technical effects
The process for synthesizing the compound of the formula (I) and the intermediate thereof provided by the invention has the beneficial effects that: the raw materials are low in price and easy to obtain, the defects of difficult separation and purification, difficult industrialization and the like are overcome, the defects that the national supervision of the hydrocarbon reduction reaction of highly toxic substances methane sulfonyl chloride, inflammable and explosive sodium azide, palladium and the like is not suitable for the amplified production steps are avoided, the total synthetic route is shortened, the waste emission is reduced, and the method is more economical and practical. The invention has high industrial application value and economic value in the aspect of preparing the compound of the formula (I) and the intermediate thereof.
Detailed Description
For a better understanding of the present invention, reference will now be made to the following examples, which are not intended to limit the scope of the present invention.
Example 1: preparation of Compound SM1
Step 1:
under the protection of nitrogen, compound SM1-1 (1.5 kg,5.27mol,1 equivalent) was dissolved in anhydrous toluene (22.5L), cooled to-70-78 ℃, n-butyllithium (2.53L, 2.50M n-hexane solution, 1.1 equivalent) was added dropwise, the reaction solution was stirred at this temperature for 1 hour, a toluene (900 mL) solution of oxetanone (455.32 g,6.32mol,1.2 equivalent) was added dropwise, and after the addition was completed, the reaction solution was slowly warmed to 25℃and kept for further reaction for 16 hours. Saturated aqueous ammonium chloride (10L) was slowly added, extracted with dichloromethane (7.5L x 2), the combined organic phases were washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, the organic solvent was removed under reduced pressure, and the crude product was purified by column chromatography over silica gel (petroleum ether/tetrahydrofuran=8/1 to 5/1) to give 1.05kg of compound SM1-2 (yield: 43.0%). 1 HNMR(400MHz，CDCl 3 )：8.86(s，2H)，5.03-4.96(m，5H)。
Step 2:
diethylaminosulfur trifluoride (432.54 g,2.68mol,354.54mL,1.55 eq.) was dissolved in anhydrous dichloromethane (600 mL) under ice-water bath protection, and a solution of compound SM1-2 (400 g,1.73mol,1 eq.) in anhydrous dichloromethane (2000 mL) was added dropwise. After the completion of the dropwise addition, the reaction solution was slowly warmed to 25℃and stirred for 1 hour. Cooling the reaction solution to 0 ℃, adding 5L of water, and using dichloromethaneAlkane (5L 3) extraction, combined organic phases dried over anhydrous sodium sulfate, filtration, removal of organic solvent under reduced pressure, separation and purification of crude product obtained by combining four batches of reaction liquid by silica gel column chromatography (petroleum ether/ethyl acetate=1/0 to 10/1), further recrystallization of the obtained product with 1.5L petroleum ether, filtration, yield 1.08kg compound SM1 (yield: 67.1%). 1 HNMR(400MHz，CDCl 3 )：8.891(s，2H)，5.18-5.05(m，4H)。
Example 2: preparation of Compound SM2
Step 3:
compound SM2-1 (12.8 kg,118.36mol,1.0 eq.) was added to N, N-dimethylformamide (10.0-15.0 kg), ethyl 2-cyanopropionate (15.0 kg,118.36mol,1.0 eq.) was added, and the reaction mixture was warmed to 100-130℃and stirred for a further 10-15 hours. The reaction mixture was cooled to room temperature, 47.2kg of methyl tert-butyl ether was added, stirring was continued at 25℃for 2-3 hours, filtration was carried out, the cake was washed with 2-5kg of methyl tert-butyl ether, and the obtained solid was dried under vacuum to give 13.1kg of Compound SM2-2 (yield: 59.0%). 1 HNMR(300MHz，DMSO_d 6 )：9.62(s，1H)，7.49-7.37(m，4H)，7.21-7.16(m，1H)，5.24(s，2H)，1.69(s，3H)。
Step 4:
to N, N-dimethylformamide (15.0-20.0 kg) was added compound SM2-2 (8.58 kg,45.35mol,1.0 eq), diisopropylethylamine (7.0 kg,54.16mol,9.4L,1.2 eq) was added, the reaction mixture was cooled to-5-15℃and N-phenylbis (trifluoromethanesulfonyl) imide (17.0 kg,47.59mol,1.05 eq) was added dropwise at this temperature, and after the completion of the addition, the reaction mixture was heated to 25℃and stirred for 10-15 hours. Adding 60-80kg of 10% sodium carbonate aqueous solution and 15.0-20.0kg of methyl tertiary butyl ether into the reaction solution, separating, washing the organic phase twice with 50-80kg of 10% sodium carbonate aqueous solution, washing three times with 50-70kg of saturated ammonium chloride aqueous solution, washing once with 50-70kg of saturated saline solution, removing the organic solvent under reduced pressure, and obtaining a crude product, and using 15L of petroleumThe ether was recrystallized and filtered, and the obtained solid was dried under vacuum to obtain 13.4kg of Compound SM2 (yield: 92.0%). 1 HNMR(300MHz，DMSO_d 6 )：7.53-7.49(m，4H)，7.41-7.38(m，1H)，5.67(s，2H)，1.89(s，3H)。
Example 3: preparation of Compound SM3
Step 5:
compound SM3-1 (49.5-50.5 kg,329.81-336.47mol,1 eq.) was added to acetyl chloride (275.0-280.0 kg,3.50-3.57kmol,10 eq.) and the reaction was warmed to 50deg.C and stirred for a further 12-24 hours. The organic solvent was removed under reduced pressure, the resulting crude product was added to methyl tert-butyl ether (185.0-190.0 kg), concentrated, repeated three times, and the crude product was further added to methyl tert-butyl ether (185.0-190.0 kg) and stirred at room temperature for 2 hours, filtered, the filter cake was washed with 37.0-40.0kg of methyl tert-butyl ether, and the filter cake was dried to give 60.7kg of compound SM3-2 (yield: 84.3%). 1 H NMR(300MHz，CDCl 3 )：5.70(s，2H)，2.25(s，6H)。
Step 6:
compound SM3-2 (60.0-60.5 kg,277.59-279.90mol,1 eq) was added to tetrahydrofuran (270.0-275.0 kg), the reaction solution was cooled to-5-5 ℃, 2-methoxyethylamine (24.0-24.5 kg,319.53-326.19mol,1.15 eq) was added dropwise, the reaction solution temperature was kept at-5-5 ℃, and after the addition was completed, the reaction solution was warmed to 65 ℃ and stirred for 2-24 hours. The organic solvent was removed under reduced pressure, and the resulting crude product was added to methyl tert-butyl ether (224.0-230.0 kg), concentrated, and repeated three times, and the crude product was further added to methyl tert-butyl ether (224.0-230.0 kg) and stirred at room temperature for 2 hours, filtered, and the filter cake was washed with 45.0-50.0kg of methyl tert-butyl ether to give 78.4kg of crude compound SM3-3 (yield: 95.8%). 1 H NMR(300MHz，DMSO_d 6 )：8.15(brs，1H)，5.45(d，J＝2.4Hz，1H)，5.37(d，J＝2.4Hz，1H)，5.26(brs，1H)，3.50(t，J＝5.4Hz，2H)，3.20(s，3H)，2.96(t，J＝5.4Hz，2H)，2.09(s，3H)，2.02(s，3H)。
Step 7:
compound SM3-3 (78.3 kg,268.84mol,1 eq.) was added to acetyl chloride (360.0-365.0 kg,4.59-4.65kmol,17 eq.) and the reaction was warmed to 50deg.C and stirred for a further 12-24 hours. The organic solvent was removed under reduced pressure, the resulting crude product was added to methyl tert-butyl ether (290.0-300.0 kg), concentrated, repeated three times, the crude product was further added to methyl tert-butyl ether (232.0-240.0 kg) and ethyl acetate (140.0-145.0 kg), washed with 315.0-320.0kg of 8% aqueous sodium bicarbonate solution, the aqueous phase was extracted 3 times with ethyl acetate (282.0-290.0 kg), the combined organic phases were washed with (315.0-320.0 kg) saturated brine, the organic solvent was removed under reduced pressure, the resulting crude product was added to ethanol (186.0-190.0 kg), concentrated, repeated two times, and 390.0-395.0kg of ethanol was added to give an ethanol solution of compound SM3-4 which was directly used for the next reaction without further purification. 1 H NMR(300MHz，DMSO_d 6 )：5.78(s，2H)，3.60(m，2H)，3.45(d，2H)，3.23(s，3H)，2.15(s，6H)。
Step 8:
an ethanol solution of the compound SM3-4 (73.5 kg,268.99mol,1 equivalent) was cooled to-5-5 ℃, acetyl chloride (150.0-155.0 kg,1.91-1.97kmol,7 equivalent) was added dropwise, and the reaction solution was warmed to 20-30 ℃ and stirred for 5-24 hours. Activated carbon (5.0-5.5 kg) was added and stirring was continued for 2-5 hours. Filtering, washing the filter cake with ethanol (115.0-120.0 kg), removing the organic solvent under reduced pressure, adding methyl tert-butyl ether (240.0-250.0 kg) into the obtained crude product, concentrating, repeating for three times, adding the crude product into methyl tert-butyl ether (240.0-250.0 kg), stirring for 2-5 hours, filtering, washing the filter cake with 100.0-105.0kg methyl tert-butyl ether, and drying to obtain 33.7kg compound SM3-5 (content: 88%, yield: 66.0%). 1 HNMR(300MHz，DMSO_d 6 )：5.58(brs，2H)，4.30(s，2H)，3.53(m，2H)，3.44(m，2H)，3.21(s，3H)。
Step 9:
under the protection of nitrogen, flaky lithium aluminum oxide (200 g,5.29mol,4 equivalent) was dissolved in anhydrous tetrahydrofuran (5000 mL), and tetrahydrofuran of compound SM3-5 (284 g,88% content, 1.32mol,1 equivalent) was added dropwiseThe reaction mixture was heated to 60-70℃and stirred for 16 hours. The reaction solution was cooled to 20-30℃and sodium sulfate decahydrate (284 g,1.32mol,1 eq.) was added successively, water (284 mL) and 20% aqueous sodium hydroxide solution (284 mL), and the reaction solution was warmed to 60℃and stirred for 1 hour. Filtration, washing of the cake twice with 4000mL of tetrahydrofuran, addition of the obtained cake to 4000mL of tetrahydrofuran and 500mL of 20% aqueous sodium hydroxide solution, addition of 500g of anhydrous sodium sulfate, filtration, combination of organic phases, combination of 41 batches of organic phases, removal of the organic solvent under reduced pressure gave 4.34kg of compound SM3-6 (content: 83%, yield: 41.2%). 1 HNMR(400MHz，DMSO_d 6 )：4.87(s，2H)，3.95-3.93(m，2H)，3.27(s，3H)，2.85-2.80(m，2H)，2.61-2.49(m，2H)，2.40-2.36(m，2H)。
Step 10:
under nitrogen protection, sulfonic acid isocyanate (614.6 g,4.34mol,3.5 equivalent) was dissolved in anhydrous 1, 4-dioxane (800 mL), cooled to 10-20 ℃, tert-butanol ((321.9 g,4.34mol,3.5 equivalent) was slowly added dropwise to a solution of 1, 4-dioxane (600 mL) under the protection of nitrogen, the internal temperature was kept at 10-20 ℃, stirring was continued for 0.5 hour after the addition was completed, the obtained solution was kept for standby use, compound SM3-6 (241 g,83% content, 1.25mol,1 equivalent) was dissolved in anhydrous 1, 4-dioxane (4000 mL), triethylamine (753 g,7.44mol,6 equivalent) was added, then the standby solution was slowly added dropwise, and after the addition of the reaction solution was completed, the reaction solution was stirred at 25 ℃ for 4 hours under the protection of nitrogen, the filter cake was washed once with anhydrous dioxane, triethylamine (213 g, 2.25 ℃ C., 1.25mol,1 equivalent) was added to 2000% ethyl acetate was removed, and ethyl acetate was removed by vacuum distillation (2000:1:2.25 equivalent), the crude ethyl acetate was removed by vacuum distillation, ethyl acetate was continuously mixed with water phase chromatography (2000:1:1.2 mL), and ethyl acetate was removed). 1 HNMR(400MHz，DMSO_d 6 )：5.35-5.32(m，1H)，4.73-4.70(m，1H)，3.52-3.49(m，2H)，3.12(s，3H)，3.12-3.08(m，1H)，3.02-2.98(m，1H)，2.86-2.82(m，2H)，2.73-2.70(m，2H)，1.53(m，9H)。
Step 11:
compounds SM3-7 (1.41 kg,71% strength, 3.0mol,1 eq.) were dissolved in N, N-dimethylformamide (5000 mL) under nitrogen, and phthaloyl potassium salt (747 g,4.0mol,1.3 eq.) was added and the reaction was warmed to 70℃and stirred for a further 8 hours. Cooling, filtering the reaction solution by diatomite, removing the organic solvent under reduced pressure, dissolving the obtained residue by 2000mL of tetrahydrofuran, adjusting the pH to 2.7-3.5 by using 0.5M aqueous hydrochloric acid solution, heating to 40 ℃ and continuously stirring for 1 hour. Cooled, extracted with methyl tert-butyl ether (4000 mL), the aqueous phase adjusted to pH 8-9 with 20% aqueous sodium carbonate, the two other batches were combined and filtered, the filter cake was washed with water and dried to give 6.0kg of compound SM3-8 (content: 60%, yield: 81.0%). 1 H NMR(400MHz，DMSO_d 6 )：7.83-7.71(m，4H)，5.25-5.22(m，1H)，4.64-4.58(m，2H)，3.52-3.46(m，2H)，3.33(s，3H)，3.24-3.20(m，1H)，3.08-3.04(m，1H)，2.95-2.88(m，1H)，2.78-2.70(m，3H)，1.38(s，9H)。
Step 12:
compounds SM5-8 (600 g,60% content, 0.92mol,1 eq.) were dissolved in ethanol (7.2L) under nitrogen, hydrazine hydrate (108.7 g,1.85mol,2 eq.) was added and the reaction was warmed to 70℃and stirred for a further 1 hour. To the crude product obtained in the step of combining 6 batches was added methyl tert-butyl ether (6000 mL), followed by cooling, filtration and removal of the organic solvent under reduced pressure, whereby 1.35kg of Compound SM3-9 was obtained (yield: 92.0%). 1 H NMR(400MHz，CDCl 3 )：4.79(s，1H)，3.54-3.52(m，1H)，3.32-3.29(m，2H)，3.20(s，3H)，3.11(s，1H)，2.70-2.66(m，1H)，2.51-2.40(m，3H)，1.99-1.95(m，1H)，1.42(s，9H)。
Step 13:
compounds SM3-12 (750 g,3.00mol,1 eq.) and vinyltrimethylsilane (601.45 g,6.00mol,870.40mL,2 eq.) were dissolved in acetonitrile (1.8L) and activated copper powder (9.53 g,150.01mmol,0.05 eq.) was added and the reaction was warmed to 65℃and stirred for a further 18 hours. The organic solvent was removed under reduced pressure, and the crude products obtained in 4 batches were separated and purified by silica gel column chromatography (eluent: 0 to 3% ethyl acetate/petroleum ether) to give 3.80kg of compound SM3-13 (yield: 90.5%). 1 H NMR(400MHz，CDCl 3 )：4.25-4.12(m，2H)，2.93-2.90(m，1H)，2.47-2.39(m，2H)，1.24-1.13(m，3H)，0.02(s，9H)。
Step 14:
compounds SM3-13 (1.27 kg,3.63mol,1 eq.) were dissolved in anhydrous tetrahydrofuran (15L) at-20deg.C, diisobutylaluminum hydride (1M in toluene, 5.44L,1.5 eq.) was slowly added dropwise, and after the addition, the reaction mixture was slowly warmed to 10deg.C and stirred for further 1 hour. Cooling, slowly dropping 5L2N hydrochloric acid aqueous solution, keeping the temperature of the reaction solution at 20 ℃ or below, extracting with ethyl acetate (8L 2), combining the extracted organic phases, washing with 10L saturated saline, drying with anhydrous sodium sulfate, filtering, and removing the organic solvent under reduced pressure to obtain 977.5g of the compound SM3-10 (yield: 88.0%). This compound was used in the next reaction without further purification.
Step 15:
compound SM3-9 (690 g,2.66mol,1 eq.) was dissolved in acetonitrile (6.5L) and compound SM3-10 (977.48 g,3.19mol,1.2 eq.) was added and the reaction was warmed to 65℃and stirred for a further 14 hours. The organic solvent was removed under reduced pressure, and the crude product obtained in the other batch was combined and purified by silica gel column chromatography (eluent: 0 to 60% ethyl acetate/petroleum ether to 5% methanol/ethyl acetate) to give 1.70kg of Compound SM3-11 (yield: 98.0%). 1 H NMR(400MHz，CDCl 3 )：6.74(s，1H)，6.50(s，1H)，5.77(s，1H)，5.64(s，1H)，4.85(s，1H)，4.48(s，1H)，3.81-3.58(m，6H)，3.41-3.38(m，2H)，3.23(s，3H)，1.19(s，9H)。
Step 16:
compound SM3-11 (2.86 kg,8.74mol,1 eq.) was dissolved in anhydrous tetrahydrofuran (22L), p-toluenesulfonic acid (3.76 kg,21.84mol,2.5 eq.) was added, and the reaction was warmed to 80℃and stirred for 2 hours. Cooled, filtered, and the filter cake was washed with methyl tert-butyl ether (300 ml. Times.2) and dried to give 3.30kg of compound SM3 (yield: 66.1%). 1 H NMR(400MHz，MeOD)：7.76-7.74(m，4H)，7.30-7.28(m，4H)，6.86-6.84(m，1H)，6.78-6.75(m，1H)，6.01-5.99(m，1H)，5.11-5.09(m，1H)，4.44-4.41(m，1H)，4.15-4.11(m，2H)，3.85-3.70(m，4H)，3.62-3.59(m，2H)，3.38(s，3H)，2.40(s，6H)。
Example 4: preparation of Compound 1
Step 17:
under nitrogen atmosphere, compound SM1 (1.0 kg,4.30mol,1 eq.) was dissolved in anhydrous dioxane (30.0L), and dibasic pinacol borate (1.2 kg,4.74mol,1.1 eq.), potassium acetate (840 g,8.62mol,2 eq.), tricyclohexylphosphorus (120 g,430.0mmol,0.1 eq.) and palladium acetate (100 g,430mmol,0.1 eq.) were added in this order, the reaction mixture was heated to 90℃and stirred for 3 hours, water (5L), SM2 (1.1 kg,3.45mol,0.8 eq.) and diphenylphosphinofferrocene palladium dichloride (300 g,430.0mmol,0.1 eq.) were added in this order, and the reaction mixture was stirred for 15 to 18 hours at this temperature. The reaction mixture was cooled to room temperature, filtered through celite, the filter cake was washed with ethyl acetate (5L), the combined filtrate was separated with saturated brine (10L), the aqueous phase was extracted with ethyl acetate (10L x 2), the combined organic phase was concentrated under reduced pressure to 30L, activated carbon (2.0 kg), anhydrous magnesium sulfate (4.0 kg) and metal eliminator (3-mercaptopropyl functional silica gel, 2.0 kg) were added, stirring was continued for 18 hours at 55 ℃, the reaction mixture was filtered through celite, the filter cake was washed with ethyl acetate (10L x 2), the organic solvent was removed under reduced pressure, the crude product obtained was added to methyl tert-butyl ether (5L), n-heptane (1L) was added, stirring was continued at room temperature for 15-18 hours, filtration was continued, the filter cake was washed with methyl tert-butyl ether (500 ml x 2), drying was carried out, the crude product obtained was added to acetonitrile (3.5L), water (15-17L) was added, stirring was continued for 15 hours at 80 ℃, filtration was continued, the filter cake was washed with water (500 ml), and the yield was 0.47% was obtained by drying the compound. 1 H NMR(400MHz，CDCl 3 )：9.20(s，2H)，7.68-7.62(m，2H)，7.57-7.53(m，2H)，7.48-7.40(m，1H)，5.29-5.13(m，4H)，3.76(brs，2H)，2.19(s，3H)。
Step 18:
compound 1-2 (0.73 kg,2.24mol,1 eq.) is dissolved in anhydrous dichloromethane (15L) under nitrogen protection, pyridine (0.54 kg,6.74mol,3 eq.) is added, cooled to 0deg.C, a solution of compound 1-3 (0.46 kg,2.92mol,1.3 eq.) in dichloromethane (1.2L) is added dropwise, and the internal temperature of the reaction solution is kept at not more than 10deg.C, and after the dropwise addition, the reaction solution is stirred continuously at that temperature for 0.5-2 hours. To the reaction solution was added 0.5N aqueous hydrochloric acid (8L), the solution was separated, the aqueous phase was extracted with methylene chloride (8L), the combined organic phases were washed with saturated brine (10L), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure to give 0.90kg of Compound 1-4 (yield: 90.0%), which was used in the next reaction without further purification. 1 H NMR(400MHz，CDCl 3 )：9.26(s，2H)，7.64-7.40(m，6H)，7.53-7.48(m，2H)，7.32-7.29(m，1H)，7.15-7.12(m，1H)，5.31-5.12(m，4H)，2.35(s，3H)。
Step 19:
compounds 1 to 4 (1.0 kg,2.24mol,1 eq.) were dissolved in anhydrous tetrahydrofuran (10L), compound SM3 (1.28 kg,2.24mol,1 eq.) was added, and a solution of sodium carbonate (1.19 kg,11.23mol,5 eq.) in water (5.0L) was added dropwise, and the reaction solution was stirred at room temperature for 20 hours. Water (6.0L) and ethyl acetate (6.0L) were added to the reaction solution, the solution was separated, the aqueous phase was extracted with ethyl acetate (6.0L x 2), the combined organic phase was washed with saturated brine (15.0L), dried over anhydrous sodium sulfate, filtered, the organic solvent was removed under reduced pressure, the crude product obtained was added to methanol (6.5L), water (13L) was added, the mixture was warmed to 40 ℃ and stirred for 2-24 hours, filtered, the cake was washed with water (2L x 2), further added to methanol (8L), water (10L) was added, the mixture was warmed to 40 ℃ and stirred for 10-48 hours, filtered, and the cake was washed with water (2L x 2), dried to give 0.93kg of compound 1 (yield: 71.6%). 1 H NMR(400MHz，MeOD)：9.27(s，2H)，7.61-7.50(m，4H)，7.49-7.42(m，1H)，6.64-6.59(m，1H)，6.56-6.50(m，1H)，5.84(m，1H)，5.32-5.21(m，2H)，5.12-5.02(m，2H)，4.34-4.18(m，2H)，3.55-3.53(t，J＝5.2Hz，2H)，3.37(s，3H)，3.14-3.06(m，2H)，2.89-2.64(m，3H)，2.55-2.50(m，1H)，2.23(s，3H)。
Experimental example 1: trkA enzyme Activity test
Experimental materials
TrkA Invitrogen-PV4114
TK detection kit Cisbio-62TK0PEJ
Detection plate Perkinelmer-6007299
Envision PerkinElmer-2104
Kinase reaction buffer
20mM Hepes(pH7.5)，10mM MgCl 2 (magnesium chloride), 1mM EGTA,0.01%Brij35,0.1mM Orthovanadate (sodium vanadate), 0.02g/mL BSA (bovine serum albumin), 2mM DTT (dithiothreitol), 1% DMSO
Experimental method
This experiment uses the homogeneous time resolved fluorescence conjugated energy transfer from Cisbio Inc.)Method) for activity detection. In the assay plate, the enzyme, biotin-labeled polypeptide substrate, ATP, and the detection compound are mixed and incubated for reaction. After the reaction, ethylenediamine tetraacetic acid was added to terminate the reaction, and at the same time, eu-labeled antibody was added, and streptavidin-labeled XL665 was reacted and detected. The data are represented by readings of fluorescence signals 665nm and 620nm, respectively, where a high ratio of 665nm/620nm indicates higher activity and a low ratio of 665nm/620nm indicates inhibited activity.
Experimental procedure
1. Compound dilution: the compound to be tested is diluted 4 times, the total concentration is 10, and the final system concentration is from 10 mu M to 0.038nM;
2. in 20mM Hepes (pH 7.5) in buffer, 10mM MgCl 2 1mM EGTA,0.01%Brij35,0.1mM sodium vanadate, 0.02g/mLBSA,2mM DTT,1%DMSO in a 10. Mu.L reaction system comprising 15nM TrkA kinase, 0.3. Mu.Mdiotin-TK peptide (biotin)Labeled tyrosine kinase substrate polypeptide), 100 μm ATP, and incubated at 23 ℃ for 120 min. The reaction sites were placed on P81 ion exchange paper (Whatman # 3698-915), the filters were thoroughly washed with 0.75% phosphoric acid, and the radiophosphorylated substrate remaining on the filters was measured. Kinase activity data are expressed as a percentage of kinase activity in the test samples compared to vehicle (DMSO) response.
3.IC 50 And curve fitting can be obtained by Graphpad software Prism 4.
Experimental results
The results are shown in Table 1.
TABLE 1 IC of the compounds of formula (I) for TrkA enzyme inhibition 50 Value of
Numbering of compounds TrkA IC 50 (nM)
A compound of formula (I) 6.64
The results show that: the compound of formula (I) has a significant TrkA enzyme inhibition effect.
Experimental example 2: cytochrome P450 isoenzyme inhibition activity test
Purpose of experiment
The inhibitory activity of the test compounds against different isoforms of the human cytochrome P450 isozymes was determined.
Experimental operation
Preparing a test compound, a standard inhibitor (100 x final concentration) and a mixed substrate working solution; the microsomes frozen in the refrigerator at-80 ℃ are taken out for thawing. Adding 2 μl of test compound and standard inhibitor solution to the corresponding sites, while adding 2 μl of corresponding solvent to the inhibitor-free control site (NIC) and Blank control site (Blank) sites; next, 20. Mu.L of the mixed substrate solution was added to the corresponding well sites except for the Blank well sites (20. Mu.L of PB was added to the Blank well sites); preparing human liver microsome solution (marking date after use and immediately returning to refrigerator), and then adding 158 μl of human liver microsome solution to all holes; pre-incubating the sample plate in a water bath at 37 ℃ to prepare a coenzyme factor (NADPH) solution; after 10 minutes, add 20. Mu.L NADPH solution to all sites, shake the sample plate evenly and incubate in 37℃water bath for 10 minutes; at the corresponding time point, the reaction was terminated by adding 400. Mu.L of cold acetonitrile solution (internal standard 200ng/mL of tolbutamide and labetalol); after the sample plates are uniformly mixed, the mixture is centrifuged at 4000rpm for 20 minutes to precipitate proteins; 200. Mu.L of supernatant was added to 100. Mu.L of water, shaken well and then transferred to LC/MS/MS for detection.
Experimental results
The results are shown in Table 3.
TABLE 3 IC for inhibition of P450 isozymes by Compounds of formula (I) 50 Value of
The results show that: the compounds of formula (I) have a lower risk of drug-drug interactions.
Experimental example 3: in vivo pharmacokinetic study after a single administration in rats
Purpose of experiment
Male SD rats were used as test animals, and the plasma concentration of the compound was measured after a single administration and the pharmacokinetic behavior was evaluated.
Experimental materials:
sprague Dawley rats (Male, 200-300g, 7-9 weeks old, shanghai Vitolihua laboratory animal Co., ltd.)
Experimental operation:
the rodent drug substitution characteristics of the test compounds were tested by standard protocols after intravenous and oral administration, in which the test compounds were formulated as clear solutions or uniform suspensions for single intravenous and oral administration to rats. The intravenous injection group solvent is ethanol and normal saline solution with a certain proportion or HP-beta cyclodextrin solution of dimethyl sulfoxide with a certain proportion (acid is regulated to pH=3-4), vortex stirring is carried out, 1mg/mL clarified solution is prepared, and microporous filter membrane is filtered for later use; the oral solvent is carboxymethyl cellulose sodium solution with a certain proportion or HP-beta cyclodextrin solution with a certain proportion of dimethyl sulfoxide (adjusting acid to pH=about 4), and after the compound to be tested is mixed with the solvent, vortex stirring is carried out to prepare 30mg/mL uniform suspension for standby. After 2mg/kg intravenous administration or 300mg/kg oral administration of rats, a certain amount of whole blood sample is collected, 3000g is centrifuged for 15 minutes, a plasma sample is obtained by separating the supernatant, 3 times of acetonitrile solution containing an internal standard is added for precipitating proteins, the supernatant is centrifugally taken, 2 times of water is added for centrifugal sampling, the supernatant is quantitatively analyzed by an LC-MS/MS analysis method for blood concentration, and Phoenix WinNonlin software (Pharsight corporation) is used for calculating drug generation parameters such as peak reaching concentration, peak reaching time, clearance, half life, area under a drug time curve, bioavailability and the like.
Experimental results:
table 5 pharmacokinetic properties of compounds of formula (I) in male rats (n=3)
Wherein C is 0 To the initial concentration, T 1/2 To eliminate half-life, vd ss Is steady state apparent distribution volume, cl is total clearance, AUC 0-inf For the area under the plasma concentration-time curve from time 0 to extrapolation to infinity, C max To reach the peak concentration, T max For peak time.
The results show that: the compounds of formula (I) have good rat pharmacokinetic properties and oral bioavailability.
Experimental example 4: in vivo pharmacokinetic study after single administration of beagle dogs
Purpose of experiment
In male beagle dogs as test animals, the compound blood concentration was determined after a single administration and the pharmacokinetic behavior was evaluated.
Experimental materials:
beagle dog (Male, 6-12 kg, older than 6 months, beijing Mas Biotechnology Co.)
Experimental operation:
the test aims to test the non-rodent drug substitution characteristics of the test compound after intravenous injection and oral administration, and the test compound is prepared into clear solution or uniform suspension in the test and is administered to beagle dogs through single intravenous injection or oral administration. The intravenous injection group solvent is HP-beta-cyclodextrin solution of dimethyl sulfoxide or ethanol, polyethylene glycol 400 and physiological saline solution of a certain proportion, vortex and ultrasonic are carried out, so as to prepare 2mg/kg clarified solution, and the clarified solution is filtered by a microporous filter membrane for later use; oral solvent is dimethyl sulfoxide with a certain proportionCyclodextrin solution or sodium carboxymethylcellulose solution with a certain proportion, mixing the compound to be tested with a solvent, and carrying out vortex and ultrasonic treatment to prepare 3mg/mL uniform suspension for later use. After intravenous administration of 2mg/kg and oral administration of 15mg/kg, a certain amount of whole blood sample is collected, centrifugation is carried out for 10 minutes at 3000g, a plasma sample is obtained by separating the supernatant, 10 times of acetonitrile solution containing an internal standard is added for precipitating protein, the supernatant is taken for sample injection by centrifugation, the blood concentration is quantitatively analyzed by an LC-MS/MS analysis method, and the drug generation parameters such as peak reaching concentration, peak reaching time, clearance, half life, area under a drug time curve, bioavailability and the like are calculated by using Phoenix WinNonlin software (Pharsight corporation).
Experimental results:
table 7 pharmacokinetic properties of compounds of formula (I) in male beagle dogs (n=3)
Wherein C is 0 To the initial concentration, T 1/2 To eliminate half-life, vd ss Is steady state apparent distribution volume, cl is total clearance, AUC 0-inf For the area under the plasma concentration-time curve from time 0 to extrapolation to infinity, C max To reach the peak concentration, T max For peak time.
The results show that: the compounds of formula (I) have good beagle pharmacokinetic properties and oral bioavailability.

Claims (20)

1. A process for the preparation of a compound of formula (I),
which comprises the following steps:
step 1: reacting a compound of formula SM3-9 with a compound of formula SM3-10 to obtain a compound of formula SM3-11,
step 2: reacting an intermediate compound obtained by reacting a compound of formula SM1 with a compound of formula 1-1 with a compound of formula SM2 to obtain a compound of formula 1-2,
wherein,
reagent P is selected from acetonitrile;
reagent S-1 is selected from potassium acetate;
the reagent S-2 is selected from tricyclohexylphosphine, 2-di-tert-butylphosphino-3, 4,5, 6-tetramethyl-2, 4, 6-triisopropyl-1, 1-biphenyl, 2- (dicyclohexylphosphino) -3, 6-dimethoxy-2-4-6-triisopropyl-1, 1-biphenyl, triphenylphosphine and 2-dicyclohexylphosphorus-2, 4, 6-triisopropylbiphenyl;
the catalyst U is selected from palladium acetate, diphenylphosphine ferrocene palladium dichloride, tetraphenylphosphine palladium, allyl palladium chloride dimer, cinnamyl palladium chloride dimer and palladium trifluoroacetate;
the base T is selected from sodium carbonate, cesium carbonate and potassium carbonate;
solvent V is selected from dioxane, methylcyclopentyl ether, toluene, methyltetrahydrofuran and tetrahydrofuran.
2. The preparation method according to claim 1, which comprises the following reaction scheme:
wherein,
reagent A is selected from 2-methoxyethylamine;
solvent B is selected from tetrahydrofuran;
reagent C is selected from acetyl chloride;
reagent D is selected from acetyl chloride;
solvent E is selected from ethanol;
the reducing agent F is selected from lithium aluminum hydride, borane tetrahydrofuran solution and borane dimethyl sulfide complex;
solvent G is selected from tetrahydrofuran;
reagent H is selected from sulfonic acid isocyanate;
reagent I is selected from tertiary butanol;
base J is selected from triethylamine and diisopropylethylamine;
solvent K is selected from dioxane and dichloromethane;
reagent L is selected from phthalimide potassium salt;
the solvent M is selected from N, N-dimethylformamide, tetrahydrofuran, methanol, dioxane and dimethyl sulfoxide;
reagent N is selected from hydrazine hydrate;
the solvent O is selected from ethanol;
reagent Q is selected from p-toluenesulfonic acid, hydrochloric acid and trifluoroacetic acid;
the solvent R is selected from tetrahydrofuran, dichloromethane and ethyl acetate;
the base W is selected from pyridine, triethylamine, diisopropylethylamine and sodium bicarbonate;
the solvent X is selected from dichloromethane, N-dimethylformamide, tetrahydrofuran and ethyl acetate;
the base Y is selected from sodium carbonate, diisopropylethylamine, triethylamine, pyridine, sodium bicarbonate, potassium carbonate and sodium hydroxide;
the solvent Z is selected from tetrahydrofuran/water, methyltetrahydrofuran, methylene chloride and methyltetrahydrofuran/water.
3. The production method according to claim 1 or 2, wherein in the step of producing the compound SM3-11, the temperature range of the reaction system is controlled to 65±5 ℃.
4. The production method according to claim 1 or 2, wherein the molar ratio of the compound SM3-9 to the compound SM3-10 is 1: 1.2-2.
5. The preparation process according to claim 1 or 2, wherein the molar ratio of compound SM1 to catalyst U is 1:0.05 to 0.1.
6. The production method according to claim 2, wherein in the step of producing the compound SM3-3, the temperature of the reaction system is controlled to be within a range of 0±5 ℃ when the compound SM3-3 is fed into the reaction system.
7. The preparation method according to claim 2, wherein the molar ratio of compound SM3-3 to reagent C is 1: 12-17.
8. The production method according to claim 2, wherein in the step of producing the compound SM3-5, the temperature of the reaction system is controlled to be within a range of 0±5 ℃ when the compound SM3-5 is fed into the reaction system.
9. The production method according to claim 2, wherein in the step of producing the compound SM3-6, the molar ratio of the compound SM3-5 to the reducing agent F is 1:2 to 4.
10. The production method according to claim 2, wherein in the step of producing the compound SM3-7, the temperature of the reaction system is controlled to be 15±5 ℃ when the compound SM3-7 is fed into the reaction system.
11. The production method according to claim 2, wherein in the step of producing the compound SM3-7, the temperature of the reaction system is controlled to be 20±5 ℃ after the completion of the reagent feeding.
12. The production method according to claim 2, wherein in the step of producing the compound SM3-7, filtration is maintained under a nitrogen atmosphere after completion of the reaction.
13. The production method according to claim 2, wherein in the step of producing the compound SM3-7, the temperature of the reaction system is controlled to be 80±5 ℃ after the completion of the reagent feeding.
14. The production method according to claim 2, wherein in the step of producing the compound SM3-8, the pH is controlled to be 2.7 to 3.5 when the acid is used for the post-treatment.
15. The production method according to claim 2, wherein in the step of producing the compound SM3-8, the post-treatment controls the temperature of the reaction system to 35±5 ℃ when the pH is adjusted.
16. The preparation method according to claim 2, wherein the molar ratio of the compound SM3-8 to the reagent N is 1:1.5 to 2.
17. The preparation method according to claim 2, wherein the molar ratio of the compound SM3-11 to the reagent Q is 1:2.5 to 4.
18. The production method according to claim 2, wherein in the step of producing the compounds 1 to 4, the temperature of the reaction system is controlled to be 5.+ -. 5 ℃ when the materials are fed into the reaction system.
19. The process according to claim 2, wherein in the step of preparing the compounds 1 to 4, the reaction time is 1.5.+ -. 0.5 hours after the completion of the reagent addition.
20. The preparation method according to claim 2, wherein the molar ratio of the compounds 1 to 4 to the base Y is 1:5.
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